Mapping Sleep's Oscillatory Events as a Biomarker of Alzheimer's Disease

Pulver, R. L.; Kronberg, E.; Medenblik, L. M.; Kheyfets, V. O.; Ramos, A. R.; Holtzman, D. M.; Morris, J. C.; Toedebusch, C. D.; Sillau, S. H.; Bettcher, B. M.; Lucey, B. P.; McConnell, B. V.

doi:10.1101/2023.02.15.528725

bioRxiv · 10.1101/2023.02.15.528725

Mapping Sleep's Oscillatory Events as a Biomarker of Alzheimer's Disease

Pulver, R. L.·Kronberg, E.·Medenblik, L. M.·Kheyfets, V. O.·Ramos, A. R.·Holtzman, D. M.·Morris, J. C.·Toedebusch, C. D.·Sillau, S. H.·Bettcher, B. M.·Lucey, B. P.·McConnell, B. V.

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Abstract

ObjectiveMemory-associated neural circuits produce oscillatory events within single-channel sleep electroencephalography (EEG), including theta bursts (TBs), sleep spindles (SPs) and multiple subtypes of slow waves (SWs). Changes in the temporal "coupling" of these events are proposed to serve as a biomarker for early stages of Alzheimers disease (AD) pathogenesis. MethodsWe analyzed data from 205 aging adults, including single-channel sleep EEG, cerebrospinal fluid (CSF) AD-associated biomarkers, and Clinical Dementia Rating(R) (CDR(R)) scale. Individual SW events were sorted into high and low transition frequencies (TF) subtypes. We utilized time-frequency spectrogram locations within sleep EEG to "map" the precision of SW-TB and SW-SP neural circuit coupling in relation to amyloid positivity (by CSF A{beta}42/A{beta}40 threshold), cognitive impairment (by CDR), and CSF levels of AD-associated biomarkers. ResultsCognitive impairment was associated with lower TB spectral power in both high and low TF SW-TB coupling (p<0.001, p=0.001). Cognitively unimpaired, amyloid positive aging adults demonstrated lower precision of the neural circuits propagating high TF SW-TB (p<0.05) and low TF SW-SP (p<0.005) event coupling, compared to cognitively unimpaired amyloid negative individuals. Biomarker correlations were significant for high TF SW-TB coupling with CSF A{beta}42/A{beta}40 (p=0.005), phosphorylated-tau181 (p<0.005), and total-tau (p<0.05). Low TF SW-SP coupling was also correlated with CSF A{beta}42/A{beta}40 (p<0.01). InterpretationLoss of integrity in neural circuits underlying sleep-dependent memory processing can be measured for both SW-TB and SW-SP coupling in spectral time-frequency space. Breakdown of sleeps memory circuit integrity is associated with amyloid positivity, higher levels of AD-associated pathology, and cognitive impairment.

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Pulver, R. L., Kronberg, E., Medenblik, L. M., Kheyfets, V. O., Ramos, A. R., Holtzman, D. M., Morris, J. C., Toedebusch, C. D., Sillau, S. H., Bettcher, B. M., Lucey, B. P., McConnell, B. V.. 2023-02-16. Mapping Sleep's Oscillatory Events as a Biomarker of Alzheimer's Disease. https://doi.org/10.1101/2023.02.15.528725

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